Abstract

Background

   Recent phase III randomized controlled trials have demonstrated that
   first-line immune checkpoint inhibitors (ICIs) improve prognosis in
   advanced HER-2-negative gastric cancer patients with programmed death
   ligand 1 (PD-L1) combined positive score (CPS) higher than 5. However,
   these findings are not confirmed in real-world settings, and the
   benefits in PD-L1 CPS < 5 patients remain controversial.

Methods

   In this multicenter, retrospective cohort study, data from across
   thirteen medical centers were analyzed by inverse probability of
   treatment weighting for matching, alongside univariate and multivariate
   COX proportional hazard regression models. Genomic and transcriptomic
   analyses were conducted to identify efficacy prognostic models and
   resistance mechanisms.

Results

   This study included 573 patients with advanced gastric cancer, 265
   treated with chemotherapy and 308 with ICIs plus chemotherapy. In the
   overall cohort and HER-2-negative patients, the combination therapy
   significantly improved progression-free survival and overall survival,
   without marked increases in severe adverse events. Notably, patients
   with PD-L1 CPS 1–4 showed significant overall survival prolongation and
   a trend towards improved progression-free survival with combination
   therapy. Patients with unknown PD-L1 status also benefitted from ICIs.
   SMARCA4 and BRCA2 mutations were more frequent in patients with
   responses, while CCNE1 and ZFHX3 alternation, alongside high “ABC
   transporters” signatures, were more common in non-responsive patients.
   A novel risk model, PGFIC, outperformed traditional biomarkers in
   predicting treatment outcomes.

Conclusions

   Adding ICIs to first-line treatment significantly prolongs survival in
   overall patients and in those with PD-L1 CPS 1–4 or unknown. This study
   also provides valuable insights into prognostic markers and resistance
   mechanisms, potentially guiding immunotherapy strategies.

Supplementary Information

   The online version contains supplementary material available at
   10.1186/s12916-024-03801-5.

   Keywords: Gastric cancer, First-line treatment, Immune checkpoint
   inhibitor, Retrospective study, Multi-omics

Background

   Gastric cancer (GC) is the fifth most common cancer and the fourth
   leading cause of cancer-related death worldwide [[81]1]. The regions
   with the highest GC incidence rates include Northeast Asia, South and
   Central America, and Eastern Europe [[82]2]. The insidious onset of GC
   often results in symptoms that are challenging to distinguish from
   benign diseases, leading to approximately 40% of patients being
   advanced stage at the initial diagnosis [[83]3]. In the past,
   chemotherapy was the standard first-line treatment for advanced GC but
   only yielded a 5-year survival rate of less than 20% and a median
   overall survival (mOS) of less than one year [[84]4]. The introduction
   of trastuzumab, targeting anti-human epidermal growth factor receptor-2
   (HER-2), has improved the mOS to over fourteen months in patients with
   HER-2-amplified advanced GC [[85]5]. However, patients with HER-2
   positivity represent only 7% to 34% of the entire GC population
   [[86]5]. In recent years, immune checkpoint inhibitor (ICIs) therapy
   has brought new hope to advanced GC, albeit in the face of various
   challenges. Several randomized controlled trials (RCTs) have shown that
   the combination of ICIs and chemotherapy significantly prolongs median
   progression-free survival (mPFS) and mOS in patients with advanced
   HER-2-negative GC, especially those with high programmed death ligand 1
   (PD-L1) expression, as measured by the combined positive score
   (CPS) ≥ 5. [[87]6–[88]8] However, there were still negative survival
   outcomes in large RCTs in advanced GC, such as KEYNOTE-062. [[89]9]. In
   the ATTRACTION-4 trial, ICI combined with chemotherapy only achieved a
   significant benefit in PFS, but failed in OS, another primary endpoint
   [[90]10].

   Whether patients with low CPS expression can benefit from immunotherapy
   remains a hotly debated topic in clinical practice. Current evidence
   supports favorable outcomes for first-line ICIs combined with
   chemotherapy compared to chemotherapy alone in RCTs for advanced GC,
   primarily obtained in studies with a large proportion of patients with
   PD-L1 CPS ≥ 5. However, there is insufficient evidence to determine
   whether patients with low PD-L1 CPS expression, including those with
   CPS < 1 or CPS 1–4, would benefit from immunotherapy [[91]9]. A
   simulated individual patient data analysis using the KMSubtraction tool
   found no significant benefit in PFS or OS for advanced GC patients with
   PD-L1 CPS 1–4 after immunotherapy [[92]11]. Actually, PD-L1’s
   predicting role is limited due to its substantial spatial and temporal
   heterogeneity, especially in small available samples that may not
   accurately represent the PD-L1 expression of the entire tumor [[93]12].
   Furthermore, different methods for detecting PD-L1 expression also
   yield inconsistent results [[94]13]. Alongside PD-L1, other predictive
   biomarkers recommended in clinical practice, including microsatellite
   instability (MSI), tumor mutation burden (TMB), and Epstein-Barr virus
   (EBV) infection, also encounter limitations in terms of specificity or
   predictive efficacy [[95]12, [96]14, [97]15]. Therefore, further
   research is urgently needed to identify more effective biomarkers that
   can accurately guide treatment decisions for advanced GC.

   Recently, real-world studies have gained increasing attention for their
   broad patient inclusivity, closer alignment to clinical reality, and
   robust practical applicability [[98]16]. However, there remains an
   absence of large-scale real-world data addressing the efficacy, safety,
   and predictive markers for the first-line ICIs in combination with
   chemotherapy versus chemotherapy alone in advanced GC so far. To bridge
   this gap, we conducted a multicenter, retrospective study to validate
   the possible effectiveness of first-line immunotherapy in this
   population. Our research focused on the relationship between the
   efficacy of ICIs and the PD-L1 CPS in a real-world setting, paying
   special attention to patients with low or unknown CPS levels.
   Additionally, we explored potential molecular markers for predicting
   efficacy and investigating the mechanisms of resistance to ICIs through
   genetic sequencing analyses.

Methods

Study design and participants

   This multicenter, retrospective, controlled study was conducted in
   thirteen grade A tertiary hospitals in Shandong Province, China,
   including Qilu Hospital of Shandong University, Jinan Central Hospital,
   Linyi People's Hospital, Linyi Cancer Hospital, Affiliated Hospital of
   Qingdao University, Qingdao Municipal Hospital, Qilu Hospital of
   Shandong University (Qingdao), The First Affiliated Hospital of
   Shandong First Medical University, The Second Affiliated Hospital of
   Shandong First Medical University, Shandong Provincial Hospital, Weihai
   Municipal Hospital, Yantai Yuhuangding Hospital, and Zibo Center
   Hospital. Patients with advanced GC or gastro-esophageal junction
   cancer (GEJC) who began first-line treatment from January 1, 2018, to
   July 15, 2022, were enrolled and were followed up until December 31,
   2022.

   Eligible patients were aged 18–85 years, with histologically confirmed
   gastric and gastro-esophageal junction adenocarcinoma, including
   metastatic or locally advanced GC/GEJC without operation indication, or
   recurrent GC/GEJC at least six months post adjuvant chemotherapy.
   Patients should have a minimum of two cycles of chemotherapy or
   chemotherapy combined with ICIs for their first-line therapy.
   Trastuzumab is allowed for patients with HER-2 positive tumor.
   Exclusion criteria include individuals with multiple primary tumors, as
   well as those lacking evaluable lesions or efficacy assessment. The
   decision to receive chemotherapy alone or chemotherapy plus ICI was
   determined by the physician, based on their clinical judgment, when
   ICIs were not yet a standardized first-line treatment for gastric
   cancer. This study followed the Strengthening the Reporting of
   Observational Studies in Epidemiology (STROBE) reporting guideline for
   observational studies.

Data collection and assessment

   Patient information was collected through the electronic medical record
   system and follow-up visits at least every three months. Imaging
   results, including CT and MRI results within 28 days before the
   patient's initial treatment, were utilized as the baseline data for
   evaluating efficacy. Tumor responses were assessed according to
   Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria
   [[99]17], and categorized as complete response (CR), partial response
   (PR), stable disease (SD), or progressive disease (PD) for patients
   with measurable lesions, and as CR, non-PR/non-PD, or PD for patients
   without measurable lesions. The objective response rate (ORR) was
   defined as the proportion of patients achieving CR or PR. PFS was
   defined as the time interval from the initiation of first-line therapy
   to PD or death from any cause. OS was defined as the time interval from
   the initiation of first-line treatment to death for any reason. Adverse
   events were assessed throughout the study according to Common
   Terminology Criteria for Adverse Events (CTCAE) version 5.0 [[100]18].
   PD-L1 CPS scoring was conducted using the 22C3 (73.7%) and SP263
   (26.3%) antibody clones, primarily based on the preferences of the